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1.
Front Endocrinol (Lausanne) ; 12: 772865, 2021.
Article in English | MEDLINE | ID: covidwho-1556281

ABSTRACT

The potential relationship between diabetes and COVID-19 has been evaluated. However, new knowledge is rapidly emerging. In this study, we systematically reviewed the relationship between viral cell surface receptors (ACE2, AXL, CD147, DC-SIGN, L-SIGN and DPP4) and SARS-CoV-2 infection risk, and emphasized the implications of ACE2 on SARS-CoV-2 infection and COVID-19 pathogenesis. Besides, we updated on the two-way interactions between diabetes and COVID-19, as well as the treatment options for COVID-19 comorbid patients from the perspective of ACE2. The efficacies of various clinical chemotherapeutic options, including anti-diabetic drugs, renin-angiotensin-aldosterone system inhibitors, lipid-lowering drugs, anticoagulants, and glucocorticoids for COVID-19 positive diabetic patients were discussed. Moreover, we reviewed the significance of two different forms of ACE2 (mACE2 and sACE2) and gender on COVID-19 susceptibility and severity. This review summarizes COVID-19 pathophysiology and the best strategies for clinical management of diabetes patients with COVID-19.


Subject(s)
Angiotensin-Converting Enzyme 2/blood , COVID-19/complications , COVID-19/drug therapy , Diabetes Complications/drug therapy , Diabetes Mellitus/drug therapy , Aged , Animals , Cardiovascular Diseases/complications , Cardiovascular Diseases/drug therapy , Comorbidity , Female , Humans , Hyperglycemia/metabolism , Hypertension , Inflammation , Insulin Resistance , Insulin-Secreting Cells/metabolism , Male , Middle Aged , Obesity/complications , Obesity/drug therapy , Renal Insufficiency, Chronic/complications , Renal Insufficiency, Chronic/drug therapy , Risk , Risk Factors , SARS-CoV-2
2.
J Diabetes Investig ; 12(12): 2126-2128, 2021 Dec.
Article in English | MEDLINE | ID: covidwho-1413728

ABSTRACT

Two recent reports denoted the potential of SARS-CoV-2 to directly infect ß-cells and the possible fate of ß-cells under COVID-19. The fight against SARS-CoV-2 will continue to develop more effective therapeutic strategies for diabetes.


Subject(s)
COVID-19/epidemiology , COVID-19/metabolism , Diabetes Mellitus/epidemiology , Diabetes Mellitus/metabolism , Insulin-Secreting Cells/metabolism , SARS-CoV-2/metabolism , Diabetes Mellitus/virology , Humans , Insulin-Secreting Cells/virology
3.
Trends Endocrinol Metab ; 32(11): 842-845, 2021 11.
Article in English | MEDLINE | ID: covidwho-1349597

ABSTRACT

The widespread extrapulmonary complications of coronavirus disease 2019 (COVID-19) have gained momentum; the pancreas is another major target for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Here, we take a closer look into potential pathological interactions. We provide an overview of the current knowledge and understanding of SARS-CoV-2 infection of the pancreas with a special focus on pancreatic islets and propose direct, indirect, and systemic mechanisms for pancreas injury as result of the COVID-19-diabetes fatal bidirectional relationship.


Subject(s)
COVID-19/metabolism , Diabetes Mellitus/metabolism , Insulin-Secreting Cells/metabolism , Acinar Cells/metabolism , Angiotensin-Converting Enzyme 2/metabolism , Glucagon-Secreting Cells/metabolism , Humans , Islets of Langerhans/metabolism , Pancreas/metabolism , Receptors, Coronavirus/metabolism , SARS-CoV-2/metabolism , Serine Endopeptidases/metabolism , Viral Tropism
4.
Cell Metab ; 33(8): 1565-1576.e5, 2021 08 03.
Article in English | MEDLINE | ID: covidwho-1343160

ABSTRACT

Emerging evidence points toward an intricate relationship between the pandemic of coronavirus disease 2019 (COVID-19) and diabetes. While preexisting diabetes is associated with severe COVID-19, it is unclear whether COVID-19 severity is a cause or consequence of diabetes. To mechanistically link COVID-19 to diabetes, we tested whether insulin-producing pancreatic ß cells can be infected by SARS-CoV-2 and cause ß cell depletion. We found that the SARS-CoV-2 receptor, ACE2, and related entry factors (TMPRSS2, NRP1, and TRFC) are expressed in ß cells, with selectively high expression of NRP1. We discovered that SARS-CoV-2 infects human pancreatic ß cells in patients who succumbed to COVID-19 and selectively infects human islet ß cells in vitro. We demonstrated that SARS-CoV-2 infection attenuates pancreatic insulin levels and secretion and induces ß cell apoptosis, each rescued by NRP1 inhibition. Phosphoproteomic pathway analysis of infected islets indicates apoptotic ß cell signaling, similar to that observed in type 1 diabetes (T1D). In summary, our study shows SARS-CoV-2 can directly induce ß cell killing.


Subject(s)
COVID-19/virology , Diabetes Mellitus/virology , Insulin-Secreting Cells/virology , Neuropilin-1/metabolism , Receptors, Virus/metabolism , SARS-CoV-2/pathogenicity , Virus Internalization , A549 Cells , Adult , Aged , Aged, 80 and over , Angiotensin-Converting Enzyme 2/metabolism , Antigens, CD/metabolism , Apoptosis , Apoptosis Regulatory Proteins/metabolism , COVID-19/complications , COVID-19/diagnosis , Case-Control Studies , Diabetes Mellitus/diagnosis , Diabetes Mellitus/metabolism , Female , Host-Pathogen Interactions , Humans , Insulin/metabolism , Insulin-Secreting Cells/metabolism , Male , Middle Aged , Receptors, Transferrin/metabolism , SARS-CoV-2/metabolism , Serine Endopeptidases/metabolism , Spike Glycoprotein, Coronavirus/metabolism
5.
Cell Metab ; 32(6): 1028-1040.e4, 2020 12 01.
Article in English | MEDLINE | ID: covidwho-1310646

ABSTRACT

Isolated reports of new-onset diabetes in individuals with COVID-19 have led to the hypothesis that SARS-CoV-2 is directly cytotoxic to pancreatic islet ß cells. This would require binding and entry of SARS-CoV-2 into ß cells via co-expression of its canonical cell entry factors, angiotensin-converting enzyme 2 (ACE2) and transmembrane serine protease 2 (TMPRSS2); however, their expression in human pancreas has not been clearly defined. We analyzed six transcriptional datasets of primary human islet cells and found that ACE2 and TMPRSS2 were not co-expressed in single ß cells. In pancreatic sections, ACE2 and TMPRSS2 protein was not detected in ß cells from donors with and without diabetes. Instead, ACE2 protein was expressed in islet and exocrine tissue microvasculature and in a subset of pancreatic ducts, whereas TMPRSS2 protein was restricted to ductal cells. These findings reduce the likelihood that SARS-CoV-2 directly infects ß cells in vivo through ACE2 and TMPRSS2.


Subject(s)
Angiotensin-Converting Enzyme 2/metabolism , COVID-19/metabolism , Diabetes Mellitus/metabolism , SARS-CoV-2/physiology , Serine Endopeptidases/metabolism , Virus Internalization , Angiotensin-Converting Enzyme 2/analysis , Angiotensin-Converting Enzyme 2/genetics , Animals , COVID-19/complications , COVID-19/genetics , Cells, Cultured , Diabetes Complications/genetics , Diabetes Complications/metabolism , Diabetes Mellitus/genetics , Gene Expression , Humans , Insulin-Secreting Cells/metabolism , Mice , Microvessels/metabolism , Pancreas/metabolism , RNA, Messenger/analysis , RNA, Messenger/genetics , Serine Endopeptidases/analysis , Serine Endopeptidases/genetics
6.
Cell Metab ; 33(4): 692-699, 2021 04 06.
Article in English | MEDLINE | ID: covidwho-1298657

ABSTRACT

Marking insulin's centennial, we share stories of researchers and clinicians whose seminal work has advanced our understanding of insulin, islet biology, insulin resistance, and diabetes. The past century of pursuing the "hormone of hormones" and advancing diabetes therapies is replete with stories of collaboration, perseverance, and triumph.


Subject(s)
Diabetes Mellitus/drug therapy , Insulin/therapeutic use , Biomedical Research/history , Cell- and Tissue-Based Therapy , Drug Delivery Systems , Glucagon-Like Peptide-1 Receptor/agonists , Glucagon-Like Peptide-1 Receptor/metabolism , History, 20th Century , History, 21st Century , Humans , Insulin/chemistry , Insulin/metabolism , Insulin Resistance , Insulin-Secreting Cells/cytology , Insulin-Secreting Cells/metabolism
7.
Nat Commun ; 12(1): 3534, 2021 06 10.
Article in English | MEDLINE | ID: covidwho-1265954

ABSTRACT

Metabolic diseases are associated with an increased risk of severe COVID-19 and conversely, new-onset hyperglycemia and complications of preexisting diabetes have been observed in COVID-19 patients. Here, we performed a comprehensive analysis of pancreatic autopsy tissue from COVID-19 patients using immunofluorescence, immunohistochemistry, RNA scope and electron microscopy and detected SARS-CoV-2 viral infiltration of beta-cells in all patients. Using SARS-CoV-2 pseudoviruses, we confirmed that isolated human islet cells are permissive to infection. In eleven COVID-19 patients, we examined the expression of ACE2, TMPRSS and other receptors and factors, such as DPP4, HMBG1 and NRP1, that might facilitate virus entry. Whereas 70% of the COVID-19 patients expressed ACE2 in the vasculature, only 30% displayed ACE2-expression in beta-cells. Even in the absence of manifest new-onset diabetes, necroptotic cell death, immune cell infiltration and SARS-CoV-2 viral infection of pancreatic beta-cells may contribute to varying degrees of metabolic dysregulation in patients with COVID-19.


Subject(s)
Angiotensin-Converting Enzyme 2/metabolism , COVID-19/pathology , Insulin-Secreting Cells/virology , Receptors, Coronavirus/metabolism , SARS-CoV-2/isolation & purification , Serine Endopeptidases/metabolism , Adult , Aged , Autopsy , Diabetes Complications/pathology , Diabetes Complications/virology , Diabetes Mellitus/pathology , Dipeptidyl Peptidase 4/metabolism , Female , HMGN Proteins/metabolism , Humans , Insulin-Secreting Cells/metabolism , Male , Middle Aged , Neuropilin-1/metabolism , Organ Specificity/physiology
8.
Cell Metab ; 33(8): 1577-1591.e7, 2021 08 03.
Article in English | MEDLINE | ID: covidwho-1240259

ABSTRACT

Recent clinical data have suggested a correlation between coronavirus disease 2019 (COVID-19) and diabetes. Here, we describe the detection of SARS-CoV-2 viral antigen in pancreatic beta cells in autopsy samples from individuals with COVID-19. Single-cell RNA sequencing and immunostaining from ex vivo infections confirmed that multiple types of pancreatic islet cells were susceptible to SARS-CoV-2, eliciting a cellular stress response and the induction of chemokines. Upon SARS-CoV-2 infection, beta cells showed a lower expression of insulin and a higher expression of alpha and acinar cell markers, including glucagon and trypsin1, respectively, suggesting cellular transdifferentiation. Trajectory analysis indicated that SARS-CoV-2 induced eIF2-pathway-mediated beta cell transdifferentiation, a phenotype that could be reversed with trans-integrated stress response inhibitor (trans-ISRIB). Altogether, this study demonstrates an example of SARS-CoV-2 infection causing cell fate change, which provides further insight into the pathomechanisms of COVID-19.


Subject(s)
COVID-19/virology , Cell Transdifferentiation , Insulin-Secreting Cells/virology , SARS-CoV-2/pathogenicity , Acetamides/pharmacology , Adolescent , Adult , Aged , Aged, 80 and over , Animals , COVID-19/mortality , Cell Transdifferentiation/drug effects , Chlorocebus aethiops , Cyclohexylamines/pharmacology , Cytokines/metabolism , Eukaryotic Initiation Factor-2/metabolism , Female , Glucagon , Host-Pathogen Interactions , Humans , Insulin/metabolism , Insulin-Secreting Cells/drug effects , Insulin-Secreting Cells/metabolism , Insulin-Secreting Cells/pathology , Male , Middle Aged , Phenotype , Signal Transduction , Tissue Culture Techniques , Trypsin/metabolism , Vero Cells , Young Adult
9.
Int J Mol Sci ; 22(5)2021 Mar 05.
Article in English | MEDLINE | ID: covidwho-1129733

ABSTRACT

While there are various kinds of drugs for type 2 diabetes mellitus at present, in this review article, we focus on metformin which is an insulin sensitizer and is often used as a first-choice drug worldwide. Metformin mainly activates adenosine monophosphate-activated protein kinase (AMPK) in the liver which leads to suppression of fatty acid synthesis and gluconeogenesis. Metformin activates AMPK in skeletal muscle as well, which increases translocation of glucose transporter 4 to the cell membrane and thereby increases glucose uptake. Further, metformin suppresses glucagon signaling in the liver by suppressing adenylate cyclase which leads to suppression of gluconeogenesis. In addition, metformin reduces autophagy failure observed in pancreatic ß-cells under diabetic conditions. Furthermore, it is known that metformin alters the gut microbiome and facilitates the transport of glucose from the circulation into excrement. It is also known that metformin reduces food intake and lowers body weight by increasing circulating levels of the peptide hormone growth/differentiation factor 15 (GDF15). Furthermore, much attention has been drawn to the fact that the frequency of various cancers is lower in subjects taking metformin. Metformin suppresses the mechanistic target of rapamycin (mTOR) by activating AMPK in pre-neoplastic cells, which leads to suppression of cell growth and an increase in apoptosis in pre-neoplastic cells. It has been shown recently that metformin consumption potentially influences the mortality in patients with type 2 diabetes mellitus and coronavirus infectious disease (COVID-19). Taken together, metformin is an old drug, but multifaceted mechanisms of action of metformin have been unraveled one after another in its long history.


Subject(s)
Diabetes Mellitus, Type 2/drug therapy , Metformin/pharmacology , Autophagy/drug effects , COVID-19/complications , COVID-19/mortality , Diabetes Mellitus, Type 2/complications , Diabetes Mellitus, Type 2/etiology , Diabetes Mellitus, Type 2/mortality , Gastrointestinal Microbiome/drug effects , Humans , Insulin-Secreting Cells/drug effects , Insulin-Secreting Cells/metabolism , Intracellular Signaling Peptides and Proteins/drug effects , Intracellular Signaling Peptides and Proteins/metabolism
10.
Front Endocrinol (Lausanne) ; 11: 596898, 2020.
Article in English | MEDLINE | ID: covidwho-1011403

ABSTRACT

Increasing evidence demonstrated that the expression of Angiotensin I-Converting Enzyme type 2 (ACE2) is a necessary step for SARS-CoV-2 infection permissiveness. In light of the recent data highlighting an association between COVID-19 and diabetes, a detailed analysis aimed at evaluating ACE2 expression pattern distribution in human pancreas is still lacking. Here, we took advantage of INNODIA network EUnPOD biobank collection to thoroughly analyze ACE2, both at mRNA and protein level, in multiple human pancreatic tissues and using several methodologies. Using multiple reagents and antibodies, we showed that ACE2 is expressed in human pancreatic islets, where it is preferentially expressed in subsets of insulin producing ß-cells. ACE2 is also highly expressed in pancreas microvasculature pericytes and moderately expressed in rare scattered ductal cells. By using different ACE2 antibodies we showed that a recently described short-ACE2 isoform is also prevalently expressed in human ß-cells. Finally, using RT-qPCR, RNA-seq and High-Content imaging screening analysis, we demonstrated that pro-inflammatory cytokines, but not palmitate, increase ACE2 expression in the ß-cell line EndoC-ßH1 and in primary human pancreatic islets. Taken together, our data indicate a potential link between SARS-CoV-2 and diabetes through putative infection of pancreatic microvasculature and/or ductal cells and/or through direct ß-cell virus tropism.


Subject(s)
Angiotensin-Converting Enzyme 2/metabolism , COVID-19/virology , Insulin-Secreting Cells/metabolism , Microvessels/metabolism , Pancreas/metabolism , SARS-CoV-2/isolation & purification , COVID-19/metabolism , COVID-19/pathology , Cells, Cultured , Cytokines/metabolism , Humans , Insulin-Secreting Cells/virology , Microvessels/virology , Pancreas/virology
12.
Cells ; 9(11)2020 11 13.
Article in English | MEDLINE | ID: covidwho-927551

ABSTRACT

The novel coronavirus disease 2019 (COVID-19) caused by the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) was declared a pandemic by the WHO on 19 March 2020. This pandemic is associated with markedly elevated blood glucose levels and a remarkable degree of insulin resistance, which suggests pancreatic islet ß-cell dysfunction or apoptosis and insulin's inability to dispose of glucose into cellular tissues. Diabetes is known to be one of the top pre-existing co-morbidities associated with the severity of COVID-19 along with hypertension, cardiocerebrovascular disease, advanced age, male gender, and recently obesity. This review focuses on how COVID-19 may be responsible for the accelerated development of type 2 diabetes mellitus (T2DM) as one of its acute and suspected long-term complications. These observations implicate an active role of metabolic syndrome, systemic and tissue islet renin-angiotensin-aldosterone system, redox stress, inflammation, islet fibrosis, amyloid deposition along with ß-cell dysfunction and apoptosis in those who develop T2DM. Utilizing light and electron microscopy in preclinical rodent models and human islets may help to better understand how COVID-19 accelerates islet and ß-cell injury and remodeling to result in the long-term complications of T2DM.


Subject(s)
Apoptosis , Coronavirus Infections/pathology , Diabetes Mellitus, Type 2/pathology , Pneumonia, Viral/pathology , Animals , Betacoronavirus/isolation & purification , COVID-19 , Coronavirus Infections/complications , Coronavirus Infections/virology , Diabetes Mellitus, Type 2/complications , Humans , Insulin-Secreting Cells/cytology , Insulin-Secreting Cells/metabolism , Metabolic Syndrome/complications , Metabolic Syndrome/pathology , Oxidative Stress , Pandemics , Pneumonia, Viral/complications , Pneumonia, Viral/virology , Renin-Angiotensin System/physiology , SARS-CoV-2
13.
Nat Metab ; 2(10): 1021-1024, 2020 10.
Article in English | MEDLINE | ID: covidwho-744385

ABSTRACT

Here we report a case where the manifestations of insulin-dependent diabetes occurred following SARS-CoV-2 infection in a young individual in the absence of autoantibodies typical for type 1 diabetes mellitus. Specifically, a 19-year-old white male presented at our emergency department with diabetic ketoacidosis, C-peptide level of 0.62 µg l-1, blood glucose concentration of 30.6 mmol l-1 (552 mg dl-1) and haemoglobin A1c of 16.8%. The patient´s case history revealed probable COVID-19 infection 5-7 weeks before admission, based on a positive test for antibodies against SARS-CoV-2 proteins as determined by enzyme-linked immunosorbent assay. Interestingly, the patient carried a human leukocyte antigen genotype (HLA DR1-DR3-DQ2) considered to provide only a slightly elevated risk of developing autoimmune type 1 diabetes mellitus. However, as noted, no serum autoantibodies were observed against islet cells, glutamic acid decarboxylase, tyrosine phosphatase, insulin and zinc-transporter 8. Although our report cannot fully establish causality between COVID-19 and the development of diabetes in this patient, considering that SARS-CoV-2 entry receptors, including angiotensin-converting enzyme 2, are expressed on pancreatic ß-cells and, given the circumstances of this case, we suggest that SARS-CoV-2 infection, or COVID-19, might negatively affect pancreatic function, perhaps through direct cytolytic effects of the virus on ß-cells.


Subject(s)
Betacoronavirus , Coronavirus Infections/complications , Coronavirus Infections/diagnosis , Diabetes Mellitus, Type 1/complications , Pneumonia, Viral/complications , Pneumonia, Viral/diagnosis , Antibodies, Viral/blood , Antibodies, Viral/immunology , Autoantibodies/blood , Autoantibodies/immunology , Betacoronavirus/immunology , Biomarkers , COVID-19 , Coronavirus Infections/immunology , Diabetes Mellitus, Type 1/diagnosis , Diabetes Mellitus, Type 1/genetics , Diabetes Mellitus, Type 1/immunology , HLA-D Antigens/genetics , HLA-D Antigens/immunology , Humans , Immunoglobulin M/immunology , Insulin/metabolism , Insulin-Secreting Cells/immunology , Insulin-Secreting Cells/metabolism , Islets of Langerhans/immunology , Male , Pandemics , Pneumonia, Viral/immunology , SARS-CoV-2 , Young Adult
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